Summary: The prion protein (PrP), which is thought to be the infectious agent in the fatal neurodegenerative diseases called transmissible spongiform encephalopathies (TSE), is expressed on many cell types including macrophages. Specific peptides derived from the PrP sequence have been examined for their potential cytotoxic and neurotoxic effects when used in vitro or in-vivo. One such peptide, the PrP106-126 fragment has been shown to mimic the pathologic isoform of prion protein and to induce a cytotoxic effect in neuronal cells. We are characterizing the role of monocytes and monocyte-derived dendritic cells in this process and determining the potential mechanism whereby this cytotoxicity can occur, by determining the ability of PrP106-126 to activate specific signalling pathways in monocytes and dendritic cells derived from elutriated human monocytes. Our data demonstrate that dendritic cells exposed to PrP106-126 undergo a rapid activation of intrinsic NFkB, as demonstrated by electrophoretic mobility shift assays. This activation of NFkB has been correlated with increases in both inflammatory cytokine messenger RNA and protein expression. We have also determined that the signaling pathway through which this activation occurs utilizes p38 and JNK, is probably not G-protein linked, but rather utilizes distinct receptors and a unique signalling pathway that may Toll-receptor related. These data demonstrate the ability of prion protein fragments to induce inflammatory cytokines through the NFkB signalling pathway and suggest a potential mechanism by which prion proteins may exert their neuro- and cytotoxicity.